This project will investigate the hypothesis that: (1) the prolonged (7th - 15th PBD's) increase core temperature which occurs in rats following full thickness scald injury to greater than or equal to 45% of the body surface area, is not dependent on endotoxin and/or other translocated mediators from the portal circulation; and (2) the major portion of the increment in core temperature is "fever" due to the inducible internal pyrogens interleukin 1 and/or 6 (IL-1, IL-6), which are of burn wound origin, and part of a prolonged acute phase response following burn injury. These pyrogens produce fever via the central nervous system (CNS) by inducing an upward shift in the central set-point for regulation of body temperature. (3) Finally, these pyrogens achieve their CNS effect by accessing their receptor sites in the interstitium of the mid-line organum vasculosum laminae terminalis (OVLT) in juxtaposition to the preoptic anterior hypothalamus (POAH). From these receptors, the signal is transduced to either a neural signal or a mediator, (prostaglandin E), either of which can cross the blood brain barrier (BBB), while pyrogens cannot. This hypothesis will be investigated using a nonseptic febrile rat burn model (greater than or equal to 45% BSA). Core temperature will be estimated using thermistors implanted in the abdomen, and the output monitored by radio receiver and recorded. Blood will be obtained for endotoxin and IL-6 assay from an implanted central line. The following interventions will be performed: l) early total excision and closure with allograft of bum wounds covering greater than or equal to 45% of the BSA in Fischer inbred rats, then sequentially monitor body temperature (TB), serum IL-6 and LPS, with calorimetry between the 7th and 15th PBD's. 2) Destroy the putative receptor sites for lL-6 by lesioning the OVLT and perform the study as in Experiment I but without wound excision. 3) Produce bilateral lesions in the POAH and assay the effect on TB, and IL-6 and LPS after burn injury. 4) Block the most likely final mediator of the increase in TB, prostaglandin E, by administering ibuprofen and subsequently assay IL-6 and LPS and measure TB. 5) Evaluate the effect of blocking IL-6, using monoclonal antibodies to IL-beta and IL-6. These studies will help to establish, in a rat model, any possible role for cytokines and the burn wound in the etiology and maintenance of the increased TB following burn injury. Chronic elevation of TB accounts for as much as 25% of the hypermetabolism following burn injury, and understanding and control of this response would aid in management of patients with large burns.